The eye normally possesses a unique physiological adaptation that regionally modifies the expression of immunity. This physiological adaptation is part of ocular immune privilege. The physiological role of immune privilege is to impart upon the eye immune protection that avoids the destructive side effects of immunogenic inflammation. Immunogenic inflammation associated with delayed hypersensitivity reactions can grossly distort the visual axis resulting in blindness. Consequently, immune protection within the eye involves a selective deficiency of delayed type hypersensitivity T-cells. To control immunogenic inflammation, the cells and neurons within the ocular microenvironment produce immunomodulating factors that regionally suppress T-cell inflammatory-mediating activities. A biochemical examination of aqueous humor has shown that some of its immunosuppressive activity is associated with alpha-melanocyte stimulating hormone (alpha-MSH). Through alpha-MSH, aqueous humor suppresses IFN-gamma production but promotes proliferation of TGF-beta-producing effector T cells. These effector T cells act as regulatory T cells in that they can suppress immunogenic inflammation mediated by other inflammatory T cells. Moreover, if such regulatory T cells respond specifically to ocular autoantigens, they can suppress the severity and incidence of autoimmune retinitis. The induction of regulatory T cells is a result of alpha-MSH influencing the ability of antigen presenting cells (APC) to activate T cells and directly on T cells responding to presented antigen. It is our plan to characterize the effects of alpha-MSH on the mechanisms of T cell activation. We will also test the possibility that an injection of either alpha-MSH itself or alpha-MSH-induced regulatory T cells can suppress the incidence and severity of ocular autoimmune disease. The results of this project will allow us to understand the molecular and cellular features of immunity within the normal eye. By understanding the activity of intraocular immunomodulatory factors, such as alpha-MSH, it will be possible to induce an immune response that promotes the elimination of pathogens and tumors without the blinding consequences of immunogenic inflammation, that prevents or cures autoimmune diseases of the eye, and that promotes success of corneal, retinal and other tissue transplants.